Versatile TPR domains accommodate different modes of target protein recognition and function

Abstract

The tetratricopeptide repeat (TPR) motif is one of many repeat motifs that form structural domains in proteins that can act as interaction scaffolds in the formation of multi-protein complexes involved in numerous cellular processes such as transcription, the cell cycle, protein translocation, protein degradation and host defence against invading pathogens. The crystal structures of many TPR domain-containing proteins have been determined, showing TPR motifs as two anti-parallel α-helices packed in tandem arrays to form a structure with an amphipathic groove which can bind a target peptide. This is however not the only mode of target recognition by TPR domains, with short amino acid insertions and alternative TPR motif conformations also shown to contribute to protein interactions, highlighting diversity in TPR domains and the versatility of this structure in mediating biological events.

Fig. 1

Schematic presentation of the domain structures of TPR-containing proteins associated with the Hsp70/Hsp90 chaperone machinery (FKBP51, FKBP52, CyP40, PP5, SGT, Hop and CHIP), peroxisomal protein movement (PEX5) and host defence (p67^phox). TPR domains are depicted in red whilst other specialised functional domains are highlighted in other various colours and labelled accordingly. FKBP FK506-binding protein, PPIase peptidylprolyl isomerase, TPR tetratricopeptide repeat, CyP40 cyclophilin 40, CsA cyclosporin A, PP5 protein phosphatase 5, SGT small glutamine-rich TPR protein, Hop Hsp-organising protein, CHIP C-terminal of Hsp70-interacting protein, PEX5 peroxin 5, p67^phox neutrophil cytosol factor 2

Fig. 2

Ribbon representations of molecular structures of TPR-containing proteins. a CyP40 and b FKBP51, FKBP52. The CsA-binding domain (CyP40) and FK regions (FKBP51 and FKBP52) are shown in green. Core TPR domains for CyP40, FKBP51 and FKBP52 are depicted in red, with the final extended helices, at the C-terminal ends of each protein, shown in yellow. c p67^phox. The N-terminal TPR domain of p67^phox (red) is shown in complex with the small GTPase Rac (yellow). The β-hairpin insertion is green, while the C-terminal extended loop (blue) is accommodated in the binding groove formed by the TPRs. d PEX5. The C-terminal TPR domain of PEX5 is shown in complex with a PTS1 peptide (black) as viewed down the long axis of the peptide. The PEX5 TPR domain corresponds to two separate TPR helical bundles comprised of TPRs 1–3 (red) and 5–7 (green), while the extended TPR4 helix is blue. Remaining structural regions are yellow. All structures were derived from the RCSB Protein Data Bank with ViewerLite 5.0